The annual worldwide influence of colorectal cancer (CRC) exceeds one million, and genes are thought to have a strong impact on CRC risk. A positive family history of CRC occurs in 20-30% of patients. Much of the predisposition to CRC remains unexplained. Aberrations in the transforming growth factor beta (TGF-beta) pathway are involved in CRC carcinogenesis, particularly mutations in TGF-beta type II receptor gene.
TGFBR1*6A, which encodes a common human TGFBR1 variant, has been previously identified and transduces TGF-β signaling less effectively than TGFBR1. Cancer risk is higher for TGFBR1*6A homozygotes than for TGFBR1*6A heterozygotes among patients with hereditary colorectal cancer and no evidence of mismatch repair deficiency. However, increased gastrointestinal tumor susceptibility has not been reported in Tgfb1+/−, Tgfbr2+/−, Smad2+/− or Smad3+/− mice, leading away from conclusions that haploinsufficiency is risk factor for cancer.
Whether haploinsufficiency of any of the TGF-β genes contributes to cancer development, including colorectal cancer development, was unknown, prior to the instant invention.